The present invention relates to the delivery of diazepam through an inhalation route. Specifically, it relates to aerosols containing diazepam that are used in inhalation therapy.
VALIUM(copyright) is a composition currently marketed for the management of anxiety disorders and the relief of anxiety symptoms. It is administered both orally and by injection. The active ingredient in VALIUM(copyright) is diazepam, which is typically provided in doses of 2 mg to 20 mg.
The delivery methods for diazepam have a number of limitations. Oral administration typically provides for a relatively long onset of action (e.g. xe2x89xa71 h). Intravenous injection, while rapidly delivering a drug, involves the discomfort and risk of infection associated with catheterization or injection. It is desirable to provide a new route of administration for diazepam that allows for a rapid onset of action without the disadvantages of catheterization or injection. The provision of such a route is an object of the present invention.
The present invention relates to the delivery of diazepam through an inhalation route. Specifically, it relates to aerosols containing diazepam that are used in inhalation therapy.
In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of diazepam. Preferably, the particles comprise at least 10 percent by weight of diazepam. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of diazepam.
Typically, the aerosol has a mass of at least 10 xcexcg. Preferably, the aerosol has a mass of at least 100 xcexcg. More preferably, the aerosol has a mass of at least 200xcexc.
Typically, the aerosol particles comprise less than 10 percent by weight of diazepam degradation products. Preferably, the particles comprise less than 5 percent by weight of diazepam degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of diazepam degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of
Typically, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 15 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 10 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 8 mg/L.
Typically, the aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.
Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.1.
Typically, the aerosol is formed by heating a composition containing diazepam to form a vapor and subsequently allowing the vapor to condense into an aerosol.
In a method aspect of the present invention, diazepam is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of diazepam; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the composition that is heated comprises at least 10 percent by weight of diazepam. More preferably, the composition comprises 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of diazepam.
Typically, the delivered aerosol particles comprise at least 5 percent by weight of diazepam. Preferably, the particles comprise at least 10 percent by weight of diazepam. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of diazepam.
Typically, the condensation aerosol has a mass of at least 10 xcexcg. Preferably, the aerosol has a mass of at least 100 xcexcg. More preferably, the aerosol has a mass of at least 200xcexc.
Typically, the delivered aerosol particles comprise less than 10 percent by weight of diazepam degradation products. Preferably, the particles comprise less than 5 percent by weight of diazepam degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of diazepam degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 3.0. Preferably, the geometric standard deviation is less than 2.5. More preferably, the geometric standard deviation is less than 2.1.
Typically, the delivered aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 15 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.2 mg/L and 10 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.5 mg/L and 8 mg/L.
Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL. More preferably, the aerosol has an inhalable aerosol particle density greater than 108 particles/mL.
Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108 particles per second. Preferably, the aerosol is formed at a rate greater than 109 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010 inhalable particles per second.
Typically, the delivered aerosol is formed at a rate greater than 0.25 mg/second. Preferably, the aerosol is formed at a rate greater than 0.5 mg/second. More preferably, the aerosol is formed at a rate greater than 1 or 2 mg/second.
Typically, the condensation aerosol delivers between 0.2 mg and 20 mg of diazepam to the mammal in a single inspiration. Preferably, between 0.35 mg and 10 mg of diazepam are delivered to the mammal in a single inspiration. More preferably, between 0.5 mg and 8 mg of diazepam are delivered to the mammal in a single inspiration.
Typically, the delivered condensation aerosol results in a peak plasma concentration of diazepam in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).
Typically, the delivered condensation aerosol is used to treat anxiety.
In a kit aspect of the present invention, a kit for delivering diazepam through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of diazepam; and, b) a device that forms a diazepam containing aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 10 percent by weight of diazepam. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of diazepam.
Typically, the device contained in the kit comprises: a) an element for heating the diazepam composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.